Metabolomics Based Prediction of Delayed Effects of Acute Radiation Exposure

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Abstract Exposure of victims to ionizing radiation due to a radiological accident or nuclear terrorism leads to the acute radiation syndrome. Since several efforts have led to the development of medical countermeasures against these acute radiation toxicities, the chance that victims survive a radiological event has significantly increased. However, in victims who survive the acute effects, there will be a latent period of months to decades before delayed injuries manifest. Late organ injury is progressively irreversible, adversely affects quality of life and may prove life-threatening. Therefore, pre-emptive identification of individuals at risk for such late effects is critical in the decision process to determine the timing and choice of the most appropriate intervention strategies. Metabolomics-based biomarker assays are fast gaining credence for clinical translation in a variety of disease settings. Our preliminary studies strongly suggest that multi-analyte profiles obtained from a high-resolution mass spectrometry platform provide robust and early indicators of radiation injury with high translational value. In this Phase I study, using a discovery-validation study design, we propose to identify anticipatory metabolic biomarkers of radiation injury to two major organs at risk for delayed complications: heart and brain. Initially, we will make use of murine models of γ-ray exposure to identify plasma and urine biomarkers that predict the extent of injury that will manifest in the heart and brain before clinical symptoms appear. We will not only discover new biomarkers, but also validate them in independent cohorts of mice. We will determine which matrix (plasma or urine) provides the best predictor for each of the organ systems (Technical Objective 1). Subsequently, we will validate these biomarkers in plasma and urine samples obtained from male and female NHPs exposed to γ- radiation and followed up long term for organ injury and survival outcomes (Technical Objective 2). FDA guidance on biomarker development and co-development will be followed to ensure regulatory considerations are taken into account at all steps in the process. Most studies in this area of research identify urine or plasma metabolites that differentiate between irradiated and unirradiated animals when measured within 96 hours after radiation. While this approach has value in determining which radiation dose one was exposed to, it does not predict someone’s risk for developing delayed radiation injuries. This project will fill this gap and be among the first to identify and validate biomarker panels of delayed radiation injuries. Successful completion of technical objectives will enable the selection of biomarker panels that would be ready for analytical validation for a kit-based assay in a subsequent Phase II application. Taken together, these studies, ultimately, will enable the development of a commercially viable kit based companion diagnostic test that can be used for identifying individuals at risk for developing delayed injuries from radiation exposure.